NO119415B - - Google Patents
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- NO119415B NO119415B NO16443666A NO16443666A NO119415B NO 119415 B NO119415 B NO 119415B NO 16443666 A NO16443666 A NO 16443666A NO 16443666 A NO16443666 A NO 16443666A NO 119415 B NO119415 B NO 119415B
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- 150000001875 compounds Chemical class 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000001448 anilines Chemical class 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical group CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- VSHTWPWTCXQLQN-UHFFFAOYSA-N n-butylaniline Chemical group CCCCNC1=CC=CC=C1 VSHTWPWTCXQLQN-UHFFFAOYSA-N 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002429 hydrazines Chemical class 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 230000002218 hypoglycaemic effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 208000013016 Hypoglycemia Diseases 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- PWUZXJRWHWASFQ-UHFFFAOYSA-N 2-(n-propylanilino)acetic acid Chemical compound CCCN(CC(O)=O)C1=CC=CC=C1 PWUZXJRWHWASFQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- SYFNFQXVWFOEAA-UHFFFAOYSA-N 2-(n-butylanilino)acetic acid Chemical compound CCCCN(CC(O)=O)C1=CC=CC=C1 SYFNFQXVWFOEAA-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- -1 glycollates Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- NPKSPKHJBVJUKB-UHFFFAOYSA-N N-phenylglycine Chemical class OC(=O)CNC1=CC=CC=C1 NPKSPKHJBVJUKB-UHFFFAOYSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- WMCGVXHCWPKOMJ-UHFFFAOYSA-N ethyl 2-(n-propylanilino)acetate Chemical compound CCOC(=O)CN(CCC)C1=CC=CC=C1 WMCGVXHCWPKOMJ-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- MMFBQHXDINNBMW-UHFFFAOYSA-N n,n-dipropylaniline Chemical compound CCCN(CCC)C1=CC=CC=C1 MMFBQHXDINNBMW-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002569 water oil cream Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Fremgangsmåte til fremstilling av forbindelser for bruk ved behandling av sukkersyke. Process for the preparation of compounds for use in the treatment of diabetes.
Foreliggende oppfinnelse vedrorer en fremgangsmåte til fremstilling av forbindelser for bruk ved behandling av sukkersyke og med formelen: The present invention relates to a method for the preparation of compounds for use in the treatment of diabetes and with the formula:
hvor where
(1) Q er en N-n-propyl- eller N-n-butylanilingruppe eller er en para-kloranilinmetylgruppe, og R p er en hydroksygruppe, (1) Q is an N-n-propyl or N-n-butylaniline group or is a para-chloroanilinemethyl group, and R p is a hydroxy group,
elleror
(2) Q er en para-toluidinmetylgruppe eller en para-kloranilinmetylgruppe, og R 2 er en metoksygruppe eller en hydrazin-gruppe, (2) Q is a para-toluidine methyl group or a para-chloroaniline methyl group, and R 2 is a methoxy group or a hydrazine group,
samt salter av slike forbindelser. Denne fremgangsmåte er kjenneteg- as well as salts of such compounds. This procedure is characteristic
net ved atnet by that
a) et anilinderivat med formelen: a) an aniline derivative of the formula:
omsettes med en forbindelse med formelen: is reacted with a compound with the formula:
hvor A er et halogenatom, R p har samme betydning som angitt ovenfor, n er 1 eller 2, og X og R"<*>"er grupper som valgt sammen med n gir en gruppe Q som definert ovenfor, eller ;b) et anilinderivat med formelen fli) som definert ovenfor, omsettes med metylakrylat for således å gi en forbindelse ;med formel fl) hvor R 2 er en metoksygruppe, og Q er én sub-stituert anilinmetylgruppe med den ovenfor angitte betydning, ;hvoretter de således tilveiebragte forbindelser om onskelig omdannes ved forestring, hydrolyse eller hydrazinering til ester-, syre- eller hydrazinderivatene av formel fl), eller om Snskelig omdannes til deres salter. ;Den metode som er angitt ovenfor under a) er beskrevet av Eade og Earl i J.fihem.Soc. 194-6, 591'Metoden under b) hvor et anilinderivat med formel f II) omsettes med m*t;yl akryl at, er omtalt i J.Chem.Soc. 1957, 4170. where A is a halogen atom, R p has the same meaning as stated above, n is 1 or 2, and X and R"<*>" are groups which, selected together with n, give a group Q as defined above, or ;b) a aniline derivative with the formula fli) as defined above, is reacted with methyl acrylate to thus give a compound ;with formula fli) where R 2 is a methoxy group, and Q is one substituted anilinemethyl group with the above-mentioned meaning, after which the compounds thus obtained if desired converted by esterification, hydrolysis or hydrazine to the ester, acid or hydrazine derivatives of formula fl), or if desired converted into their salts. The method indicated above under a) is described by Eade and Earl in J.fihem.Soc. 194-6, 591' The method under b) where an aniline derivative of formula f II) is reacted with m*t;yl acrylic at, is discussed in J.Chem.Soc. 1957, 4170.
Det er funnet at administrasjon av en forbindelse med formel fl) til visse forsoksdyr folges av en markert hypoglycemi, og det er funnet at effektive hypoglycemiske doser ligger under det tok-siske nivå. It has been found that administration of a compound of formula fl) to certain laboratory animals is followed by marked hypoglycemia, and effective hypoglycemic doses have been found to be below the toxic level.
Forbindelse med formel fl) er i stand til å danne salter med forskjellige syreforbindelser, de kan f.eks. danne hydroklorider, sulfater, laktater, glykollater, isetionater, tartrater, citrater, metansulfonater eller p-toluensulfonater. Forbindelser med formel (I) hvor R 2er en hydroksygruppe kan også danne salter med basiske forbindelser,•og det kan f.eks. dannes piperazin-, dietylamin-, nat-rium- eller kalsiumsalter. Compound with formula fl) is able to form salts with various acid compounds, they can e.g. form hydrochlorides, sulfates, lactates, glycollates, isethionates, tartrates, citrates, methanesulfonates or p-toluenesulfonates. Compounds of formula (I) where R 2 is a hydroxy group can also form salts with basic compounds,• and it can e.g. piperazine, diethylamine, sodium or calcium salts are formed.
Ved foreliggende fremgangsmåte tilveiebringes de nye"forbindelser med formel fl), nemlig: N-fenyl-N-n-propylglycin, N-n- butyl-N-fenylglycin, metyl-3-p-toluidinpropionat, 3-P-toluidinpropion-hydrazid, 3-P-klor-anilinpropionsyre, metyl-3-p-kloranilinpropionat°63-P-kloranilinpropionhydrazid eller farmasoytiske akseptable salter av disse forbindelser. The present method provides the new "compounds of formula fl), namely: N-phenyl-N-n-propylglycine, N-n-butyl-N-phenylglycine, methyl-3-p-toluidine propionate, 3-P-toluidine propion hydrazide, 3-P -chloroanilinepropionic acid, methyl-3-p-chloroanilinepropionate°63-P-chloroanilinepropionhydrazide or pharmaceutically acceptable salts of these compounds.
For å måle forandringen i blodglukose-konsentrasjonen frembragt ved administrasjon av visse N-fenylglycinderivater til for-søksdyr, ble nedenfor angitte forsok foretatt. Fn forbindelse som gir en senkning av blodglukose-konsentrasjonen i forsoksdyr, sies å gi en hypoglycemisk reaksjon, og nevnte forbindelse sies å utvise hypoglycemisk aktivitet. Ved forsoket ble blandinger inneholdende forsQksforbindelsen administrert oralt til normale, fastede marsvin. Blodglukose-konsentrasjoner ble bestemt ved hjelp av den standardi-serte glukose-oksydase-peroksydasemetode i opp til 7 1/2 time etter dosering. In order to measure the change in the blood glucose concentration produced by the administration of certain N-phenylglycine derivatives to experimental animals, the experiment described below was carried out. A compound which produces a lowering of the blood glucose concentration in experimental animals is said to produce a hypoglycaemic reaction, and said compound is said to exhibit hypoglycaemic activity. In the experiment, mixtures containing the test compound were administered orally to normal, fasted guinea pigs. Blood glucose concentrations were determined using the standardized glucose-oxidase-peroxidase method for up to 7 1/2 hours after dosing.
De oppnådde resultater er oppfort i tabellen nedenfor, og hvert tall for hypoglycemisk reaksjon representerer gjennomsnittet for tre marsvin og er sammenlignet med virkningene til de kjente forbindelsene tolbutamid og fenformin. Den orale dose er gitt i mg forsoksforbindelse per kg legemsvekt av forsoksdyr. Den maksimale hypoglycemiske reaksjon er den laveste blodglukose-konsentrasjon etter administrasjon av forsoksforbindelse uttrykt i prosent av blodglukose-konsentras jonen like f6r administrasjon. De laveste tallene i tabellen indikerer således en h6y hypoglycemisk aktivitet. Den mid-lere maksimale hypoglycemiske reaksjon er definert som gjennomsnittet av den maksimale hypoglycemiske reaksjon for hvert dyr i gruppen. The results obtained are listed in the table below, and each figure for hypoglycemic reaction represents the average for three guinea pigs and is compared with the effects of the known compounds tolbutamide and phenformin. The oral dose is given in mg of test compound per kg body weight of test animal. The maximum hypoglycemic reaction is the lowest blood glucose concentration after administration of the test compound expressed as a percentage of the blood glucose concentration immediately before administration. The lowest numbers in the table thus indicate a high hypoglycaemic activity. The mean maximal hypoglycemic response is defined as the average of the maximal hypoglycemic response for each animal in the group.
De ovenfor angitte resultater viser at forsoksforbindel-sene ga en tydelig hypoglycemisk reaksjon i forsoksdyrene, og at forbindelsene fremstilt ifolge oppfinnelsen har storre og gunstigere aktivitet enn de kjente forbindelsene. The above-mentioned results show that the experimental compounds produced a clear hypoglycemic reaction in the experimental animals, and that the compounds produced according to the invention have greater and more favorable activity than the known compounds.
En forbindelse med den generelle formel I eller et saltA compound of the general formula I or a salt
av denne kan brukes i farmasøytiske preparater som oppløsninger, sus-pensjoner eller faste blandinger for oral, parenteral eller rektal administrasjon, og disse preparater kan fremstilles ved hjelp av kjente fremgangsmåter. of which can be used in pharmaceutical preparations such as solutions, suspensions or solid mixtures for oral, parenteral or rectal administration, and these preparations can be prepared using known methods.
For oral administrasjon kan fine pulvere eller granulater av saltet inneholde fortynningsmidler og disperserende og overflateaktive forbindelser, og kan administreres sammen med vann eller en sirup, nevnte salt kan videre i torr tilstand anvendes i kapsler eller i en ikke-vandig suspensjon når man har anvendt en suspenderende forbindelse, det kan anvendes i tabletter når bindestoffer og smoremidler er anvendt eller i en suspensjon, en olje eller en vann-olje-emulsjon når man samtidig anvender smaksstoffer, konserverings-midler, suspenderende, fortykkende og emulgerende forbindelser. Granulatene eller tablettene kan også belegges. For oral administration, fine powders or granules of the salt may contain diluents and dispersing and surface-active compounds, and may be administered together with water or a syrup, said salt may further be used in a dry state in capsules or in a non-aqueous suspension when one has used a suspending compound, it can be used in tablets when binders and lubricants are used or in a suspension, an oil or a water-oil emulsion when flavorings, preservatives, suspending, thickening and emulsifying compounds are used at the same time. The granules or tablets can also be coated.
For parenteral•administrasjon kan en forbindelse med formel I eller et salt av denne anvendes i sterile vandige injeksjons-opplos-ninger som ytterligere kan inneholde antioksyderende stoffer, buffere, bakteriostater eller forbindelser som gjor oppløsningen isotonisk i blodet. Hvis det er nodvendig, så kan injeksjonsopplosninger også fremstilles av sterile piller, granulater eller tabletter som kan inneholde fortynningsmidler, disperserende og overflateaktive forbindelser, samt binde- og smoremidler. For parenteral administration, a compound of formula I or a salt thereof can be used in sterile aqueous injection solutions which may further contain antioxidant substances, buffers, bacteriostats or compounds which make the solution isotonic in the blood. If necessary, injection solutions can also be prepared from sterile pills, granules or tablets which may contain diluents, dispersing and surface-active compounds, as well as binders and lubricants.
En forbindelse med formel I eller et salt av denne kan anvendes i suppositorier ved at det inkorporeres i et suppositorisk basisstoff. A compound of formula I or a salt thereof can be used in suppositories by incorporating it into a suppository base substance.
Foreliggende oppfinnelse illustreres ved folgende eksempler. The present invention is illustrated by the following examples.
Eksempel 1 - Fremstilling av N- fenyl- N- n- propylglycin Example 1 - Preparation of N-phenyl-N-n-propylglycine
N,N-di-propylanilin og etylbromacetat ble omsatt for opp-nåelse av N-fenyl-N-n-propylglycinetylester som hadde et kokepunkt på l82°C - l86°C ved 40 mm- Denne ester ble hydrolysert med alkali og etterfølgende nøytralisering med syre ga N-fenyl-N-n-propylglycin som etter omkrystallisering fra metanol, dannet hvite bladformede krystaller med et smeltepunkt på 93°-93.5°C. N,N-di-propylaniline and ethyl bromoacetate were reacted to obtain N-phenyl-N-n-propylglycine ethyl ester which had a boiling point of 182°C - 186°C at 40 mm. This ester was hydrolyzed with alkali and subsequent neutralization with acid gave N-phenyl-N-n-propylglycine which, after recrystallization from methanol, formed white leaf-shaped crystals with a melting point of 93°-93.5°C.
Eksempel- 2 - Fremstilling av N- butyl- N- fenylglycinExample-2 - Preparation of N-butyl-N-phenylglycine
N-butylanilin ble kondensert med etylkloracetat ved hjelpN-butylaniline was condensed with ethyl chloroacetate using
av standard-metoden. En fraksjon som kokte i området 150°-176°C/l4 mm, ble hydrolysert med natriumhydroksyd og den vandige fasen ble separert og bragt til pH 5 ved tilsetning av saltsyre. Glycinforbindelsen separerte som et krystallinsk fast stoff, som ved omkrystallisering fra cykloheksan ga hvite bladformede krystaller med smeltepunkt 86°- 87°C. of the standard method. A fraction boiling in the range 150°-176°C/l4 mm was hydrolysed with sodium hydroxide and the aqueous phase was separated and brought to pH 5 by addition of hydrochloric acid. The glycine compound separated as a crystalline solid, which on recrystallization from cyclohexane gave white leaf-shaped crystals of melting point 86°-87°C.
Eksempel 3 - Fremstilling av metyl- 3- P- toluidinpropionatExample 3 - Preparation of methyl-3-P-toluidine propionate
p-toluidin (26.8 g), metylakrylat (27.5 g)°g iseddikp-toluidine (26.8 g), methyl acrylate (27.5 g) °g glacial acetic acid
(25 ml) ble oppvarmet i et bad ved l60°-170°C i 8 timer. Ved destillasjon ble det oppsamlet en fraksjon (33.8 g) ved l82°-l88°C ved 26 (25 ml) was heated in a bath at 160°-170°C for 8 hours. By distillation, a fraction (33.8 g) was collected at 182°-188°C at 26
mm, og ny destillasjon ga et kokepunkt på 172°-176°C ved 18 mm, n^ I.536I. Denne fraksjon besto av metyl-3-p-toluidinpropionat og utfelte seg som et fast stoff med et smeltpunkt på 55°-57°C, hvilket ved omkrystallisering fra metanol dannet hvite bladformede krystaller med smeltepunkt 59°-60°C. mm, and fresh distillation gave a boiling point of 172°-176°C at 18 mm, n^ I.536I. This fraction consisted of methyl-3-p-toluidine propionate and precipitated as a solid with a melting point of 55°-57°C, which on recrystallization from methanol formed white leaf-shaped crystals with a melting point of 59°-60°C.
Eksempel 4 - Fremstilling av 3-^ P- kloranilinpropionsyreExample 4 - Preparation of 3-^P-chloraniline propionic acid
Tilsetning av p-kloranilin (31.9 g) til metylakrylat (27.5g^ ble foretatt som angitt i eksempel 3«Produktet, metyl-3-p-klorani-linpropionat (33.8 g) destillert ved 194°-200°C ved 20 mm og stivnet og det faste stoff hadde et smeltepunkt på 55°-57°C hvilket smeltepunkt ikke ble hevet ved omkrystallisering fra cykloheksan. Addition of p-chloroaniline (31.9 g) to methyl acrylate (27.5 g) was carried out as indicated in Example 3. The product, methyl 3-p-chloroaniline propionate (33.8 g) distilled at 194°-200°C at 20 mm and solidified and the solid had a melting point of 55°-57°C which melting point was not raised by recrystallization from cyclohexane.
Esteren (5 g), metanol (3 ml) og en oppldsning av natriumhydroksyd (2.5 g) i vann (30 ml) ble oppvarmet under tilbakelop i 10 minutter. Konsentrert saltsyre ble tilsatt for å bringe oppløsningen til pH 4. Det utfelte faste stoff ble oppsamlet (4.3 g), torket og omkrystallisert fra benzen. 3-p-kloranilinpropionsyre krystalliserte i form av lysegule nålformede krystaller med smeltepunkt 120.5° 121.5°C The ester (5 g), methanol (3 ml) and a solution of sodium hydroxide (2.5 g) in water (30 ml) were heated under reflux for 10 minutes. Concentrated hydrochloric acid was added to bring the solution to pH 4. The precipitated solid was collected (4.3 g), dried and recrystallized from benzene. 3-p-chloroaniline propionic acid crystallized in the form of light yellow needle-shaped crystals with melting point 120.5° 121.5°C
FSlgende eksempler ble foretatt ved hjelp av lignende me-toder: The following examples were made using similar methods:
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3667665A GB1153883A (en) | 1965-08-26 | 1965-08-26 | Biologically Active N-Phenylamino Acid Derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO119415B true NO119415B (en) | 1970-05-19 |
Family
ID=10390278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO16443666A NO119415B (en) | 1965-08-26 | 1966-08-25 |
Country Status (10)
| Country | Link |
|---|---|
| BE (1) | BE685944A (en) |
| BR (1) | BR6682333D0 (en) |
| ES (1) | ES330532A1 (en) |
| FR (1) | FR5881M (en) |
| GB (1) | GB1153883A (en) |
| IL (1) | IL26354A (en) |
| LU (1) | LU51820A1 (en) |
| MC (1) | MC609A1 (en) |
| NL (1) | NL6612079A (en) |
| NO (1) | NO119415B (en) |
-
1965
- 1965-08-26 GB GB3667665A patent/GB1153883A/en not_active Expired
-
1966
- 1966-08-17 IL IL2635466A patent/IL26354A/en unknown
- 1966-08-24 BR BR18233366A patent/BR6682333D0/en unknown
- 1966-08-24 BE BE685944D patent/BE685944A/xx unknown
- 1966-08-24 ES ES0330532A patent/ES330532A1/en not_active Expired
- 1966-08-25 NO NO16443666A patent/NO119415B/no unknown
- 1966-08-25 LU LU51820D patent/LU51820A1/xx unknown
- 1966-08-25 MC MC646A patent/MC609A1/en unknown
- 1966-08-26 FR FR74318A patent/FR5881M/fr not_active Expired
- 1966-08-26 NL NL6612079A patent/NL6612079A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BR6682333D0 (en) | 1973-12-04 |
| MC609A1 (en) | 1967-04-26 |
| FR5881M (en) | 1968-03-18 |
| NL6612079A (en) | 1967-02-27 |
| ES330532A1 (en) | 1967-06-16 |
| LU51820A1 (en) | 1967-02-27 |
| GB1153883A (en) | 1969-05-29 |
| IL26354A (en) | 1970-12-24 |
| BE685944A (en) | 1967-02-24 |
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